The project is conducted as a collaboration among the Tuberculosis Research Section of LCID, NIAID, the Korean Ministry of Health, Welfare and Familys National Masan Tuberculosis Hospital (NMTH) and Yonsei Universitys College of Medicine of the Republic of Korea. These collaborators have worked together to establish the International Tuberculosis Research Center (ITRC) that manages both financial and scientific activities within the laboratory facilities. The hospital is globally unique for its concentration of drug-resistant TB patients (over 900 in-patients per year) and the adjacent center is equipped with a fully functional Biosafety Level 3 laboratory facility. Specific protocol-driven investigations underway include; (1) NIAID 05-I-N069: A Natural History Study of Multidrug-Resistant TB Stains and Host Susceptibility Genes in Korean Patients with Pulmonary TB. This study seeks to characterize MDR and XDR tuberculosis isolates and their contribution to human disease and has over 750 subjects currently enrolled in 2009. (2) NIAID 07-I-N041: A Randomized, Double-blind, Placebo-controlled Pilot Study of Metronidazole Combined with Antituberculous Chemotherapy vs. Antituberculous Chemotherapy with Placebo in Subjects with Multi-drug Resistant Pulmonary Tuberculosis. The importance of anaerobic activity in candidate TB drugs is under investigation in this study. In 2009, the trial closed to enrollment after 33 patients enrolled because of concerns about side-effects, but follow up of these subjects continues. (3) NIAID 08-I-N167: A Phase 2a, Randomized, 2 Arm, Open-label, Clinical Trial of the Efficacy of Linezolid Combined with Antituberculous Therapy in Subjects with Extensively Drug-Resistant (XDR) Pulmonary Tuberculosis. The major aim of this study is to evaluate the efficacy, safety and tolerability of one of the drugs of last resort for XDR TB patients, linezolid (LZD, Zyvox, Pfizer). For the moment LZD is infrequently used in TB patients because of its prohibitive cost and adverse-effects but the emergence of XDR TB is spurring doctors into off-label, uncontrolled use in salvage therapy for the few patients that can afford it. This trial opened to enrollment in December 2008 and has enrolled 10 patients with XDR TB in 2009. (4) NIAID 09-I-N061;Pharmacokinetics of Standard First and Second Line anti-TB Drugs in the Lung and Lesions of Subjects Elected for Resection Surgery. This study of the differential penetration of tuberculosis chemotherapeutics into pulmonary tubercular lesions is poised to open. The study will focus determining the relationship between pathology and drug penetration in the types of lesions commonly seen in TB patients. The Natural History study of MDR and XDR TB has allowed a number of basic biology questions about the differences in highly drug resistant and drug sensitive tuberculosis to be addressed. This includes a collaborative effort with the Genomic Institute of the Novartis Foundation to sequence a panel of XDR and drug sensitive Mtb isolates to characterize the changes in MDR and XDR isolates that make them unique beyond their mutations in the drug resistance alleles. Several investigations into possible new diagnostic tools are also underway that will assess the presence of fragments of Mtb in easily accessible humans samples such as urine and exhaled breath condensate in point of care tests. Similar efforts are being made to detect Mtb drug resistance alleles in sputum samples so that effective therapy can be prescribed at the initiation of therapy rather than 3 to 4 months after drug treatment begins. Other studies are pursuing the contribution of specific Mtb molecules to pathogenesis, disease severity, and treatment outcome.